Inherited bone marrow failure syndromes (IBMFs) are a molecularly heterogeneous group of genetically-determined syndromes with severe clinical behavior, dependent primarily on deficient production of blood cells in the bone marrow, with risk of clonal progression to hematopoietic neoplasia. They are associated with very significant morbidity, ranging from life-threatening infections to extrahematopoietic signs, but the major cause of mortality is blood cancer, in particular myeloid neoplasms. Other cancers are also observed, especially in some IBMFs (1–7).

While there are some surprising cases with relatively few disease symptoms, IBMFs belong to most debilitating diseases of childhood, associated with low quality of life and significant mortality (3, 7–9). The specific problems include cytopenias and their complications, especially severe infections and transfusion-dependence. There are also frequent features of immunodeficiency and immune dysregulation exceeding that expected purely due to low leukocyte count such as occasional features of combined immunodeficiency and atypical infections in patients with for example GATA2 or SAMD9/L defects. There are syndrome-specific, extrahematopoietic manifestations including growth failure, neurological deterioration, skin abnormalities, gastrointestinal and pancreatic disorders, lung disease, skeletal abnormalities and others. Life expectancy is much shorter than in general population (1, 2, 4, 6, 7, 10).

The prevalence of IBMFs is not well known, as the IBMFs field and rate of diagnosis is much changing as a consequence of rapid improvement of availability of modern genetic diagnostics and awareness of the disorders. A new IBMF syndrome is described every few years. Some authors estimate the cumulative prevalence at approximately 65 per million live births, but under-diagnosis is likely. The most prevalent IBMFs are believed to be Fanconi Anemia (FA) and Diamond-Blackfan Anemia (DBA), roughly at 1: 150–000 births (3–5, 11, 12). On the other hand, there is a steep rise in the number of patients with newly described SAMD9/L deficiency syndrome, and the cumulative IBMFs prevalence might be much higher than initially thought (13, 14).

With very few exceptions IBMFs are monogenic disorders due to pathogenic variants in genes with potential impact on hematopoiesis (Table 1). In a small proportion of cases there is a strong suspicion of an inherited syndrome but no clear molecular diagnosis. The disrupted molecular pathways are widely varied and include transcriptional regulation of differentiation, deficient growth factor signaling, telomere maintenance, ribosome biogenesis, RNA processing, DNA repair, and other phenomena. Some of these have a degree of specificity for one hematopoietic lineage (such as erythropoiesis failure in DBA or agranulocytosis in severe congenital neutropenia <SCN>), other cause multilineage cytopenia/dysplasia. There are syndromes with minimal symptoms beyond hematopoietic syndrome (such as some forms of SCN or inherited thrombocytopenia) or severe abnormalities in multiple systems (telomere-biology disorders/dyskeratosis congenital <TBD/DC> or Shwachman-Diamond syndrome <SDS>) (10–15), Figure 1.

For several decades allogeneic hematopoietic stem cell transplantation (HSCT) has been and largely remains the only curative modality in inherited bone marrow failure syndrome. The indications are individualized and remain disease and disease-phase specific because of significant transplant-related morbidity and difficulty to gather high-level medical evidence of appropriate quality and volume in this heterogeneous group of rare disorders. HSCT is a high-risk procedure, and the risk might be aggravated by severe complications of myeloablative conditioning in some syndromes. While HSCT is currently the only definite approach, there is a significant rate of transplant-related mortality, and in some patients quality of life post HSCT might be very low due to for example chronic Graft-versus-Host Disease (GvHD) (8, 9, 16). There are also IBMFs-specific hazards that include in particular the increased risk of secondary solid cancer. Because of these pre- and post-transplant considerations and lack of high-level evidence, there is a lack of stringent criteria for pre-emptive HSCT prior to myeloid neoplasia and apart from disease-guided data the practice varies center-to-center and patient-to-patient. Also some patients might be not eligible for transplant or lacking a suitable donor (3, 6–9, 11, 12, 16, 17). This area and HSCT indications and practices are also impacted by the gradual introduction of gene therapies for IBMFs, but that remains developmental at the moment and have low impact on general management.

Medical non-transplant therapies have played an important role in several IBMFs from the early stages of the development of this area of hematology. Their impact varies from nearly curative treatment in Diamond–Blackfan Anemia (DBA), through supportive measure to control complications, to experimental treatment aimed at impacting the natural course of the disease. Accordingly, their part is fundamental in some of the disorders and quite minimal in others (3, 12, 18, 19). The role of medical non-cellular therapies in IBMFs may be subject to change, because of the discovery of new syndromes or new pathomechanisms of the established syndromes, potentially accumulating data from a so far limited number of available clinical trials and the emergence of new technologies in medicine. In general their impact might be diminishing due the progress in gene therapy, on the other hand there might be some new clinically useful interventions due to the progress in drug-repurposing and approaches such as targeted degraders (1–3, 7, 11, 12, 14, 18, 20).

The medical therapies can be used as a mainstay of therapy, bridge therapy to transplantation, peri- or post-transplantation and may, at least theoretically, have varied aims. The potential aims include: amelioration of the hematological phenotype, improvement of other organ function, improved growth and development, diminishing the risk of myeloid neoplasm or other cancer, control of infections or autoimmune manifestations (3, 11, 12, 20).

Following the introduction of the biology/mechanisms of the major classes of relevant agents the non-cellular therapies will be presented here with focus on clinical use in a disease-specific manner, and that divided into well-established and emerging/experimental approaches, this is also summarized in Table 1. This topic was reviewed in 2017 by Calado et al, but the knowledge expanded since that time (3).

Glucocorticosteroids are among the best known and most frequently used drugs in medicine and their biology and pharmacology are well described in basic medical textbooks and thus this is only very briefly described here. In a snapshot, glucocorticosteroids bind to the glucocorticoid receptor, resulting in nuclear translocation of the complex, binding DNA at glucocorticoid response elements and activating gene transcription (21). On the other hand, why glucocorticosteroids are effective in DBA, despite over 60 years of clinical experience, is much less obvious and the knowledge is expanding parallel to the expanding science of DBA. It is generally believed that glucocorticoids ‘unblock’ erythropoiesis at the erythroid progenitor level, the precise description and of the process and mechanisms remains elusive because of varied systems and markers used in relevant studies. The major cellular and molecular abnormalities in DBA include translational dysfunction, increased Inflammatory signaling pathway, unbalanced globin/heme synthesis, dysregulated autophagy, p53 activation and cell cycle arrest, and according to various reports all this pathways are to some extent corrected by glucocorticosteroids, but the data on precise mechanisms remains inconclusive. This complex pleiotropic mode is also surprising and difficult to apply taking into account the wide genetic/molecular and clinical heterogeneity of DBA. Still, the response to glucocorticoids and its perseverance is not universal and better understanding of the key erythropoiesis corrective mechanism may boost clinical practice (3, 12, 22–24). The practical considerations of glucocorticoid use in DBA are included below and are extensively presented and discussed elsewhere in recent recommendations (12, 23).

Androgens have been used for several decades in IBMFs, mainly telomeropathies and also FA due to their beneficial effects on erythrogenesis and telomere regulation. The potential role of anabolic steroids in IBMFs was first based on the observation, early in the 20th century, of some cases of remission in young boys with aplastic anemia/marrow failure at the onset of puberty (18, 20, 25–28). They are used with varied success to treat patients who are not HSCT candidates or bridge those awaiting HSCT. Similarly to glucocorticosteroids, anabolic steroids act mainly through the interaction with androgen receptors in a DNA binding-dependent manner to regulate gene transcription. The effects on hematopoiesis in the setting of BMF are postulated to be related through several different pathways. The mechanisms include increased production of erythropoietin and up-regulation of erythropoietin receptor expression on erythroid progenitors, hepcidin inhibition resulting in increased iron mobilization, telomere elongation in hematopoietic stem cells (HSC) via binding to the estrogen response elements (ERE) present in the TERT gene promoter and modulation of bone marrow microenvironment. The evidence for telomere elongation following danazol treatment in dyskeratosis congenita is well documented (29). These affected pathways remain not well defined and are believed to cumulatively translate into improved cell survival and proliferation, and clinically beneficial effects on immune cell populations differentiation. There is a pharmacological and biological heterogeneity of androgens, with oxymetholone and danazol most frequently described in IBMFs (3, 18, 19, 25, 26, 30–33). The side effects are well documented and include virilization, acne, enlargement of penis or clitoris, premature closure of epiphyses and resultant short stature, behavioral changes such, cholestasis, hepatic tumors and hypertension. Danazol appears to have relatively favorable toxicity profile (20, 28). Disease-specific considerations are presented below.

The two best-known thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, were licensed FDA for treatment of immune thrombocytopenia (ITP) in 2008. Since that time their use is steeply increasing and they are now widely used by hematologists around the world in ITP, but also in severe aplastic anemia, hepatitis C patients undergoing treatment with interferon-ribavirin and developmentally in post-chemotherapy thrombocytopenia, inherited thrombocytopenia, graft failure post hematopoietic stem cell transplantation and other indications. Romiplostim and eltrombopag both bind to the thrombopoietin (TPO) receptor, resulting conformational change in the TPO receptor, activation of the JAK/STAT pathway, and improving megakaryocyte progenitor proliferation as well as expansion and maintenance of hematopoietic stem cells (HSC). There are some differences between the two agents related to their binding sites in the TPO receptor and this extensively reviewed and discussed elsewhere (34–36). There are also reports suggesting that eltrombopag promotes C-NHEJ DNA repair in hematopoietic stem cells and this enhanced DNA repair may result in enhanced HSC genome stability with potential applications in FA (37–39). The applications of TPO-R in IBMFs are rather narrow and developmental, and are described in disease-sections below.

Granulocyte colony stimulating factor (G-CSF) is a glycoprotein initially discovered due to its ability to stimulate proliferation of bone marrow neutrophil progenitors in vitro. G-CSF is encoded by the CSF3 gene and can be produced by different tissues. G-CSF binds to a single receptor (G-CSFR; CSFR3) on the surface of target cells and it activates signaling associated with proliferation, differentiation, survival and other features of granulocytes. G-CSF supports the division and differentiation of myeloid precursors and promotes neutrophil maturation leading to increased neutrophil counts in peripheral blood. G-CSF is routinely used to ameliorate of chemotherapy-associated neutropenia (40).

Phase I–III clinical trials demonstrated that G-CSF increases neutrophil counts in SCN and some other bone marrow failures. G-CSF use significantly increased rates of survival of children with SCN and is in clinical use since 1980s (41–43). Disease-specific applications are presented below.

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis) is a rare severe immunodeficiency caused by gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Multiple immune cellular compartments are affected in WHIM syndrome leading to defects in specific immunity, lymphopenia, neutropenia, and recurrent and specific (e.g. HPV-related warts) infections. Neutropenia is related to myelokathexis, which is a retention of neutrophils in the bone marrow caused by hyperactivity of CXCR4 and down-stream signaling effects. CXCR4 antagonist plerixafor, mainly licensed and used for hematopoietic stem cell mobilization to peripheral blood in transplantology, was demonstrated to correct cytopenia, reduce infections, including HPV, and improve quality of life of WHIM-patients (44–48). This is a successful example of mechanism-driven drug repurposing. Importantly, while plerixafor requires subcutaneous injections, another CXCR4 antagonist effective in WHIM, mavorixafor is administered orally (49). This is presented in a disease-specific manner below.

Studies in FA-animal and human models indicated that increased levels of reactive oxygen species (ROS) and high vulnerability of hematopoietic progenitors to ROS play a significant role in the pathogenesis of bone marrow failure in FA. Quercetin is plant-derived flavonoid with antioxidant properties. Its mechanisms include directly scavenging free radicals, catalysis of electron transport in the xanthine/xanthine-oxidase pathway, chelating metal ions and inhibiting lipid peroxidation (50). Quercetin was shown to reduce spontaneous and diepoxybutane (DEB)-, formaldehyde- and acetaldehyde-induced cell cycle arrest in cells from patients with FA and was postulated to have a potential to alleviate bone marrow failure and solid cancer risk, justifying entry into low-phase clinical trials (3).

Ataluren belongs to a class of Translational readthrough-inducing drugs (TRIDs) that have been designed to suppress nonsense mutations in inherited monogenic disorders. TRIDs misread the premature termination signal by inserting a near-cognate amino acid in the place of the premature termination codon to continue translation and produce a full-length polypeptide This group of agents is known for relatively long but recently received renewed interest. Phase I, II and III clinical trials, including nonsense mutation mediated Cystic Fibrosis (CF) and nonsense mutation mediated Duchenne muscular dystrophy (DMD) individuals, demonstrated the long-term safety, changes in the expression of full-length target proteins and benefits relative to placebo of ataluren. Ataluren (PTC Therapeutics) was conditionally approved for use in Duchenne muscular dystrophy (DMD) in Europe in 2014 (51). Currently, the marketing authorization in Europe has been withdrawn (on 28 March 2025), following the opinion issued by EMA, which recommended to not renew the authorization because the effectiveness of the medicine has not been confirmed. The FDA is continuing the review of ataluren therapy specifically for individuals with nonsense mutation Duchenne (DMD). These regulatory situation may negatively impact potential use in IBMFs. Preclinical data in non-sense mutation Shwachaman-Diamond syndrome models demonstrated SBDS protein re-expression in different cellular linages following ataluren exposure. This was associated with improved ribosome biogenesis, reduced p53 levels and improved myeloid differentiation in SBDS cells (52–54). There is also single-report of ataluren effects in an FA model (55).

Metformin, a guanidine derivative, is a widely used oral antidiabetic drug with well-defined safety profile. There have been many attempts of metformin repurposing is several diseases. There are multiple cellular consequences of metformin administration but the antidiabetic effect is likely mainly related to the induction of activation of adenosine 5′-monophosphate–activated protein kinase (AMPK). Metformin was tested in preclinical FA models and tested clinically in the FA setting based on the potentially beneficial effects of the activation of AMPK on hematopoiesis and scavenging reactive aldehydes that are toxic to bone marrow cells in several IBMFs (3, 56–58).

Neutropenia in GSD type 1b and SCN-4 were demonstrated to be the consequence of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) accumulation in granulocytes caused by the loss of G6PT1 or G6PC3 that normally collaborate to destroy this metabolite. Toxic concentrations of 1,5AG6P inhibit hexokinase activity, lead to poor glucose utilization and eventually cell death in both disorders.

The realization of the neutrophil loss mechanism in GSD type 1b and G6PC3-deficiency, motivated preclinical attempts at 1,5AG6P reduction, with an inhibitor of renal glucose transporter Sodium-glucose co-transporter-2 (SGLT2) yielding spectacular hematological recovery effect in murine models. Further, this approach was successfully attempted in patients with GSD type 1b and G6PC3-deficienciency using off-label empagliflozin. Re-purposing of this antidiabetic drug is an elegant example of mechanism-driven medical intervention (42, 59, 60).

Restoring or enhancing activity of telomerase, which is a ribonucleoprotein (RNP) enzyme that adds telomere repeat sequences to the 3’ end of telomeres, in cells of patients with telomere-biology disorders has been long considered a potential therapeutic intervention in TBD to achieve telomere elongation (61, 62). One of the approaches studied in preclinical models over the last decade was prevention of human telomerase RNA component (hTR) RNA decay, which is mediated by PAPD5 oligoadenylation executed by exonuclease EXOSC10 (PAPD5h adds 3’ oligo(A) tails to promote substrate recognition by EXOSC10) (63, 64). It was shown that using human embryonic stem cells (hESCs) with a dyskerin mutation (DKC1_A353V) and defective telomere maintenance that reduction of PAPD5 levels led to improvement in telomerase activity, telomere elongation and features of improved hematopoietic potential (65, 66).

This is summarized and presented in Table 2.